Inflammation is a series of defensive response process caused in the tissues, induced by the applied injurious events (inflammatory stimuli) on any parts of a human body. When the tissues are damaged by inflammatory stimuli that could be caused by bacterial infections, immunological responses or physical injuries, the tissues respond (acute inflammation) to the stimuli, followed by excluding the stimuli to repair the damages. Alternatively, if the exclusion is difficult, the damages are progressed to induce continuously tissue swelling (chronic inflammation). Those inflammatory responses are well known to be associated with several diseases, and various mediators are known to be associated with each step during the inflammation process, constituted with activation of various cells and interactions with each other.
PLA(2) is a diverse class of enzymes, catalyzing preferentially the hydrolysis of the sn-2 acyl-ester of glycerophospholipids, that are major components of cell membranes, to liberate fatty acids. It is also well known that the PLA(2)s are responsible for deacylation-reacylation process required for cell membrane repair and maintenance, and the hydrolyzed products, as well as the further metabolites, are lipid mediators with strong diverse physiological activities. The liberated product, arachidonic acid with some activity as mediator, is further metabolized in respective inflammation-associated cells to prostaglandins, thromboxanes, lipoxins, leukotrienes, etc., which induce characteristic physiological responses, respectively (Irvine, R., Biochemical Journal 204: 3–16 (1982).). The other product, lysophosphatidylcholine not only plays roles as mediator, but also is utilized as a precursor of platelet activating factor (hereinafter referred to as PAF). These lipid mediators play an essential role to maintain homeostasis of living organisms, however, when they produced to excessive amounts under sick conditions associated with inflammation, they could cause adversely effects. In fact, steroidal anti-inflammatory drugs and various non-steroidal anti-inflammatory drugs (hereinafter referred to as NSAIDs) are known to interfere with the eicosanoid cascade, have been widely used in clinical therapy. As PLA(2) is positioned at the upstream of the eicosanoid cascade and is believed to be the rate-limiting step in the generation of these lipid mediators, this enzyme has been expected to be the promising target for research and development of novel anti-inflammatory drugs (Glaser, K. B., Advances in Pharmacology 32: 31–66 (1995).).
Recently, numerous PLA(2)s have been identified and rapidly become a large superfamily consisted of more than 15 isozymes are subdivided into four groups, on the basis of the protein structures and the characteristics in the enzymatic activities(Dennis, E. A., Trends in Biochemical Science, 22: 1–2 (1997), and Balsinde, J. et al, Annual Review of Pharmacology and Toxicology, 39: 175–189 (1999), etc.). Among them, it is noted that only the particular isozymes are shown high specificity against arachidonyl-phospholipids, as well as the enzymatic activity of the particular isozymes are selectively enhanced in a case of inflammatory disorder. As the examples for such inflammation-associated PLA(2)s, group IV-cytosolic PLA(2) (hereinafter referred to as IV-cPLA(2); molecularweight 85 kDa) and the subtypes IIA, IID, V and X of secretory PLA(2) (hereinafter referred to as sPLA(2); molecular weight 14 kDa) may be exemplified. Among these, IV-cPLA(2) is particularly considered as the responsible isozyme for producing the lipid mediators in the inflammatory diseases, which is supported by findings from the ‘knockout’ (IV-cPLA(2)−/−)mice (Uozumi, N. et al, Nature 390: 619–622 (1997), Bonventre, J. V. et al, Nature 390: 622–625 (1997), and Nagase, T. et al, Nature Immunology1: 42–46 (2000).). Therefore, the enhanced lipid mediators production under sick conditions could be suppressed by inhibiting IV-cPLA(2) activity, thereby facilitating remedy and/or prevention of the inflammatory diseases. Such diseases can be exemplified as following: anaphylaxis induced by various inflammatory stimuli, septic shock, fever and pain; respiratory diseases, such as bronchitis, pneumonia, and adult respiratory distress syndrome; digestive diseases, such as inflammatory intestine disorder, Crohn's disease, ulcerative colitis, hepatitis, and nephritis; cardio-vascular diseases, such as vasculitis and arteriosclerosis; allergic inflammatory diseases, such as rhinitis, asthma and atopic syndromes; and auto-immune diseases such as rheumatism; ischemia/reperfusion injuries, such as cerebral infarction and myocardial infarction; nerve degenerative diseases, solar keratosis, psoriasis, and the like.
However, as no drug has been developed yet, which shows remedial effects in the clinical therapies by inhibiting the enzyme activity, it is desired to develop such a new drug that can specifically and comprehensively control the lipid mediators production in inflammatory diseases, with excellent therapeutic and preventive effects.
In WO97/05135, as oxa(thia)zolidine compounds having activity of inhibiting the PLA(2) activity, the compounds represented by the following formula are disclosed.

In addition, 2-imino-4-oxothiazolidine compounds represented by the following chemical formula is disclosed in WO93/10789.

Furthermore, it is described in Musser, J. H., et al, Journal of Medicinal Chemistry 30: 2097–2093(1987). and GB 2183641 that the compounds represented by the following chemical formula show anti-inflammatory activities, etc. by Leukotriene D4 antagonistic effects.

As for oxazolidine compounds relevant to this invention, (4-methyl-5-phenyl-2-oxazolidinylidene)-propane dinitrile and the process for preparation thereof are disclosed in Huche, M. & Lhommet, G., Journal of Heterocyclic Chemistry 23 (3): 701–4(1986).

In addition, the compounds represented by the following chemical formula are disclosed in the catalogue for manufactured goods dealt by ChemDiv, Inc. or ChemStar, Ltd.

(wherein R represents ethyl or n-propyl)
Furthermore, the compounds represented by the following chemical formula and the process for preparation thereof are disclosed in Hosomi, A., et al, Journal of Organic Chemistry 55: 5308–5310(1990).
(wherein R1, R2 OR R3 represents hydrogen, methyl, ethyl or benzyl)
As for thiazolidine compounds relevant to this invention, the compounds represented by following chemical formula and the use for photo-polymerization initiator thereof are disclosed in Jpn. Pat. Appln. KOKAI publication No. Sho 53-152091.

However, it has not been known so far that those oxa(thia)zolidine compounds have PLA(2) inhibitory activity or anti-inflammatory activity.